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1.
J Immunol ; 195(2): 426-30, 2015 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-26056254

RESUMEN

Mast cells play critical roles in allergic responses. Calcium signaling controls the function of these cells, and a role for actin in regulating calcium influx into cells has been suggested. We have previously identified the actin reorganizing protein Drebrin as a target of the immunosuppressant 3,5-bistrifluoromethyl pyrazole, which inhibits calcium influx into cells. In this study, we show that Drebrin(-/-) mice exhibit reduced IgE-mediated histamine release and passive systemic anaphylaxis, and Drebrin(-/-) mast cells also exhibit defects in FcεRI-mediated degranulation. Drebrin(-/-) mast cells exhibit defects in actin cytoskeleton organization and calcium responses downstream of the FcεRI, and agents that relieve actin reorganization rescue mast cell FcεRI-induced degranulation. Our results indicate that Drebrin regulates the actin cytoskeleton and calcium responses in mast cells, thus regulating mast cell function in vivo.


Asunto(s)
Citoesqueleto de Actina/inmunología , Actinas/inmunología , Anafilaxia/inmunología , Mastocitos/inmunología , Neuropéptidos/inmunología , Receptores de IgG/inmunología , Citoesqueleto de Actina/química , Citoesqueleto de Actina/patología , Actinas/genética , Anafilaxia/inducido químicamente , Anafilaxia/genética , Anafilaxia/patología , Animales , Calcio/metabolismo , Señalización del Calcio , Degranulación de la Célula/inmunología , Regulación de la Expresión Génica , Inmunoglobulina E/administración & dosificación , Inmunoglobulina E/química , Inmunosupresores/farmacología , Mastocitos/patología , Ratones , Ratones Noqueados , Neuropéptidos/genética , Pirazoles/farmacología , Receptores de IgG/genética , Albúmina Sérica/química , Albúmina Sérica/inmunología
2.
J Virol ; 87(9): 5311-5, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23449792

RESUMEN

Maribavir (MBV) inhibits Epstein-Barr virus (EBV) replication and the enzymatic activity of the viral protein kinase BGLF4. MBV also inhibits expression of multiple EBV transcripts during EBV lytic infection. Here we demonstrate, with the use of a BGLF4 knockout virus, that effects of MBV on transcription take place primarily through inhibition of BGLF4. MBV inhibits viral genome copy numbers and infectivity to levels similar to and exceeding levels produced by BGLF4 knockout virus.


Asunto(s)
Antivirales/farmacología , Bencimidazoles/farmacología , Regulación hacia Abajo/efectos de los fármacos , Infecciones por Virus de Epstein-Barr/virología , Regulación Viral de la Expresión Génica/efectos de los fármacos , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Ribonucleósidos/farmacología , Proteínas Virales/metabolismo , Línea Celular , Genoma Viral/efectos de los fármacos , Herpesvirus Humano 4/fisiología , Humanos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/genética , Replicación Viral/efectos de los fármacos
3.
Int J Biochem Cell Biol ; 43(8): 1228-39, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21558014

RESUMEN

Mast cells play a critical role in the development of the allergic response. Upon activation by allergens and IgE via the high affinity receptor for IgE (FcɛRI), these cells release histamine and other functional mediators that initiate and propagate immediate hypersensitivity reactions. Mast cells also secrete cytokines that can regulate immune activity. These processes are controlled, in whole or part, by increases in intracellular Ca(2+) induced by the FcɛRI. We show here that N-(4-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide (BTP2), a pyrazole derivative, inhibits activation-induced Ca(2+) influx in the rat basophil cell line RBL-2H3 and in bone marrow-derived mast cells (BMMCs), without affecting global tyrosine phosphorylation of cellular proteins or phosphorylation of the mitogen-activated protein kinases Erk1/2, JNK and p38. BTP2 also inhibits activation-induced degranulation and secretion of interleukin (IL)-2, IL-3, IL-4, IL-6, IL-13, tumor necrosis factor (TNF)-α, and granulocyte macrophage-colony stimulating factor (GM-CSF) by BMMCs, which correlates with the inhibition of Nuclear Factor of Activated T cells (NFAT) translocation. In vivo, BTP2 inhibits antigen-induced histamine release. Structure-activity relationship analysis indicates that substitution at the C3 or C5 position of the pyrazole moiety on BTP2 (5-trifluoromethyl-3-methyl-pyrazole or 3-trifluoromethyl-5-methyl-pyrazole, respectively) affected its activity, with the trifluoromethyl group at the C3 position being critical to its activity. We conclude that BTP2 and related compounds may be potent modulators of mast cell responses and potentially useful for the treatment of symptoms of allergic inflammation.


Asunto(s)
Anilidas/farmacología , Calcio/metabolismo , Mastocitos/efectos de los fármacos , Tiadiazoles/farmacología , Animales , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Citocinas/inmunología , Citocinas/metabolismo , Liberación de Histamina/efectos de los fármacos , Liberación de Histamina/inmunología , Humanos , Mastocitos/inmunología , Mastocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/antagonistas & inhibidores , Factores de Transcripción NFATC/metabolismo , Fosforilación , Ratas , Transducción de Señal
4.
Int J Biochem Cell Biol ; 42(2): 337-45, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19948240

RESUMEN

Store-operated calcium channels are plasma membrane Ca(2+) channels that are activated by depletion of intracellular Ca(2+) stores, resulting in an increase in intracellular Ca(2+) concentration, which is maintained for prolonged periods in some cell types. Increases in intracellular Ca(2+) concentration serve as signals that activate a number of cellular processes, however, little is known about the regulation of these channels. We have characterized the immuno-suppressant compound BTP, which blocks store-operated channel mediated calcium influx into cells. Using an affinity purification scheme to identify potential targets of BTP, we identified the actin reorganizing protein, drebrin, and demonstrated that loss of drebrin protein expression prevents store-operated channel mediated Ca(2+) entry, similar to BTP treatment. BTP also blocks actin rearrangements induced by drebrin. While actin cytoskeletal reorganization has been implicated in store-operated calcium channel regulation, little is known about actin-binding proteins that are involved in this process, or how actin regulates channel function. The identification of drebrin as a mediator of this process should provide new insight into the interaction between actin rearrangement and store-operated channel mediated calcium influx.


Asunto(s)
Calcio/metabolismo , Neuropéptidos/genética , Neuropéptidos/metabolismo , Actinas/metabolismo , Animales , Células CHO , Canales de Calcio/metabolismo , Cricetinae , Cricetulus , Retículo Endoplásmico/metabolismo , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Células Jurkat , Lisina , Neuropéptidos/química , Neuropéptidos/deficiencia , Pirazoles/química , Pirazoles/metabolismo , ARN Interferente Pequeño/genética
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